Onset of action of antidepressants

Abstract

Most benefit is evident in the first two weeks, not six, as conventional wisdom says

Recent guidance from the National Institute for Health and Clinical Excellence (NICE) says that antidepressant drugs should be offered routinely to all patients with depression of at least moderate severity and recommends a selective serotonin reuptake inhibitor as first line treatment.¹ The NICE guidance goes on to state that “Patients started on antidepressants should be informed about the delay in onset of effect.” This reflects conventional wisdom, but is it time to revisit this idea?

Speed of onset of the actions of antidepressants is clinically important for several reasons. Delayed onset means that depression, its associated disability, and for some patients the potential risk of suicide continue. Early onset of effects may improve future compliance and thus outcomes.

When tricyclic antidepressants were first introduced in the 1950s delays in antidepressant effects were not reported. Indeed, researchers on early tricyclic antidepressants asserted that they usually started to work within the first few days of treatment.^{2 3} Later clinical experience suggested, however, that the drugs did not act immediately. The ensuing debate continued into the 1970s. By the mid-1970s, animal models suggested that the dissociation of acute biochemical changes induced by antidepressant treatment and the therapeutic action were due to the development of subsensitivity in the postsynaptic monoamine receptor.^{4 5} In animal models, these changes became apparent only after dosing with antidepressants over a similar period to that taken for clinical efficacy to develop. In the 1980s, a series of pooled clinical studies seemed to confirm this delayed onset of action.⁶ Since then, increasingly refined neurobiological theories of the action of antidepressants have incorporated this delay.⁷

This message is largely unchanged, despite the development of newer antidepressants, such as the selective serotonin reuptake inhibitors, and even though newer antidepressants can often be started at a therapeutic dose, rather than titrated upwards over two to three weeks, as is necessary with the older tricyclic antidepressants to minimise adverse effects.

Research on this question is hampered by lack of an agreed definition of onset of action.⁸ This is particularly true in clinical practice, where it may be difficult to distinguish between signs of response and side effects. For example, sedation may relieve symptoms but it is not directly related to the medicine's antidepressant properties. Recently, however, several studies have challenged the assumption of a delay in the onset of antidepressant action.^{9 10 11}

A meta-analysis of 76 double blind placebo controlled trials of antidepressant treatment for depression in 2005 found that 60% of overall improvement occurred during the first two weeks and that half of all patients who respond to a six week trial respond in the same period.¹⁰ More recently, a meta-analysis of placebo controlled trials of selective serotonin reuptake inhibitors suggested that therapeutic response is greatest in the first week, with a gradual decline in the size of benefit over successive weeks of treatment.¹¹ One third of the total effect seen at six weeks was apparent in the first week.¹¹ As the studies were placebo controlled trials, this improvement was unlikely to be a placebo effect.

These recent findings raise further questions. Is speed of therapeutic benefit with antidepressants a class effect, and do differences occur within classes? Do some symptoms respond quicker than others? Does early response predict future response and, if so, should we routinely review response earlier and change treatment if no response occurs in the first week or two? Does this phenomenon apply only to a subset of the population and is it genetically determined? Should we be encouraging patients to anticipate early relief from symptoms and, if so, is there a risk of disappointment if benefit is delayed?

Until studies are specifically designed to measure the onset of action of antidepressants, results from meta-analyses of studies not designed for this purpose should be treated with caution. We suggest that future studies should look for subsets of symptoms that may be ameliorated earlier than others and seek to discover how this is mediated. In the meantime, if these findings are correct it is good news for many patients with depression treated with antidepressants. But these results are unlikely to alter clinical practice until these additional questions are answered.